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Summaries for Cutaneous T Cell Lymphoma

NIH Rare Diseases
:49
Cutaneous T-cell lymphomas (CTCLs) are a group of disorders characterized by an abnormal accumulation of cancerous T-cells (a type of white blood cells) in the skin resulting in an itchy, red rash that can thicken or form a tumor. CTCLs belong to a larger group of disorders known asnon-Hodgkin's lymphomas. The most common types are mycosis fungoides and Sézary syndrome. In some cases, cancerous T-cells may spread to the lymph nodes and eventually to other body tissues and organs, potentially resulting in life-threatening complications. The specific signs and symptoms vary from person to person. The exact cause of these conditions is unknown.
Last updated: 9/27/2011

FDA approved drugs:

Indications and Usage:17
ISTODAX is a histone deacetylase (HDAC) inhibitor indicated for: Treatment of cutaneous T-cell lymphoma (CTCL) in patients who havereceived at least one prior systemic therapy (1). Treatment of peripheral T-cell lymphoma (PTCL) in patients who havereceived at least one prior therapy (1).These indications are based on response rate. Clinical benefit such asimprovement in overall survival has not been demonstrated (1).

DrugBank Targets:
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Mechanism of Action:17

Target: histone deacetylase (HDAC)Action: inhibitorFDA: Romidepsin is a histone deacetylase (HDAC) inhibitor. HDACs catalyze the removal of acetyl groups from acetylated lysine residues in histones, resulting in themodulation of gene expression. HDACs also deacetylate non-histone proteins, such as transcription factors. In vitro, romidepsin causes the accumulation of acetylatedhistones, and induces cell cycle arrest and apoptosis of some cancer cell lines with IC50 values in the nanomolar range. The mechanism of the antineoplastic effect ofromidepsin observed in nonclinical and clinical studies has not been fully characterized.

Indications and Usage:17
TARGRETIN (bexarotene) is a retinoid indicated for the treatment ofcutaneous manifestations of cutaneous T-cell lymphoma in patients who arerefractory to at least one prior systemic therapy. (1)

Indications and Usage:17
UVADEXâ¢ (methoxsalen) Sterile Solution is indicated for extracorporeal administration withthe UVARâ¢ XTSâ¢ or THERAKOSâ¢ CELLEXâ¢ Photopheresis System in the palliativetreatment of the skin manifestations of Cutaneous T-Cell Lymphoma (CTCL) that isunresponsive to other forms of treatment.

Target: DNAAction: inhibitor of DNA synthesis, cell division, and epidermal turnoverFDA: The exact mechanism of action of methoxsalen is not known. The best-known biochemicalreaction of methoxsalen is with DNA. Methoxsalen, upon photoactivation, conjugates and formscovalent bonds with DNA which leads to the formation of both monofunctional (addition to asingle strand of DNA) and bifunctional adducts (crosslinking of psoralen to both strands ofDNA). Reactions with proteins have also been described. The formation of photoadducts resultsin inhibition of DNA synthesis, cell division and epidermal turnover.For the palliative treatment of Cutaneous T-Cell Lymphoma, Photopheresis consists of removinga portion of the patient's blood and separating the red blood cells from the white cell layer (buffycoat) by centrifugation. The red cells are returned to the patient and the UVADEXâ¢ SterileSolution is then injected into the instrument and mixed with the buffy coat. The instrument thenirradiates this drug-cell mixture with ultraviolet light (UVA light, 320-400 nm) and returns thetreated cells to the patient. See the appropriate Operator's Manual for details of this process.Although extracorporeal phototherapy exposes less than 10% of the total body burden ofmalignant cells to methoxsalen plus light, some patients achieve a complete response. Animalstudies suggest that the photopheresis may activate an immune-mediated response against themalignant T-cells.Use of the UVARâ¢ and UVARâ¢ XTSâ¢ Systems after oral administration of methoxsalenwere previously approved for the treatment of Cutaneous T-Cell Lymphoma. Interpatientvariability in peak plasma concentration after an oral dose of methoxsalen ranges from 6 to 15fold. UVADEXâ¢ is injected directly into the separated buffy coat in the instrument in anattempt to diminish this interpatient variability and to improve the exposure of the cells to thedrug.Methoxsalen is reversibly bound to serum albumin and is also preferentially taken up byepidermal cells. Methoxsalen is rapidly metabolized in humans, with approximately 95% of thedrug excreted as metabolites in the urine within 24 hours.Systemic administration of methoxsalen followed by UVA exposure leads to cell injury. Themost obvious manifestation of this injury after skin exposure is delayed erythema, which maynot begin for several hours and peaks at 48-72 hours. The inflammation is followed over severaldays to weeks, by repair which is manifested by increased melanization of the epidermis andthickening of the stratum corneum.The total dose of methoxsalen delivered in UVADEXâ¢ is substantially lower (approximately200 times) than that used with oral administration. More than 80% of blood samples collected30 minutes after reinfusion of the photoactivated buffy coat had methoxsalen levels belowdetection limits of the assay (<10 ng/ml), and the mean plasma methoxsalen concentration wasapproximately 25 ng/ml.

Indications and Usage:17
VALCHLOR is an alkylating drug indicated for the topical treatmentof Stage IA and IB mycosis fungoidesâtype cutaneous Tâcelllymphoma in patients who have received prior skinâdirected therapy(1).Â Â